The present invention relates to a composition for the treatment and protection of animals which are infested with parasites or likely to be infested with them.
More particularly, the aim of the invention is to control and eliminate the parasites which infest pets, and especially cats and dogs.
Pets are often infested with one or more of the following parasites:
cat and dog fleas (Ctenocephalides felis, Ctenocephalides sp. and the like),
ticks (Rhipicephalus sp., Ixodes sp., Dermacentor sp., Amblyoma sp. and the like)
galls (Demodex sp., Sarcoptes sp., Otodectes sp. and the like).
Fleas cause an animal a great deal of stress and are harmful to its health. Moreover, fleas are also vectors of pathogenic agents, such as dog tapeworm (Dipylidium caninum), and can also attack man.
Similarly, ticks can also cause an animal stress and be harmful to its health. They can also be harmful to man. However, the most serious problem of ticks is that they are the vector of pathogenic agents which may affect the animal as much as man. Among the major diseases which need to be avoided, mention may be made of borrelioses (Lyme disease caused by Borrelia burgdorferi), babesioses (or piroplasmoses caused by Babesia sp.) and rickettsioses (also known as Rocky Mountain spotted fever). Ticks can also release toxins with paralysing and inflammatory properties, these toxins occasionally being fatal.
Lastly, galls are particularly difficult to combat since there are very few active substances which act on these parasites, and they require frequent treatment.
Many more or less active and more or less expensive insecticides exist. However, phenomena of resistance are often associated with their use, as is the case, for example, with carbamates, organophosphorus compounds and pyrethroids.
Moreover, international patent application WO-A-87/03781 and European patent application EP-A-0,295,117 describe a large family of N-phenyl-pyrazoles with a very broad spectrum of activity, including antiparasitic activities.
The object of the invention is to provide novel antiparasitic compositions for the treatment and protection of animals, these compositions being of great efficacy while at the same time being easy to use.
Another object of the invention is to provide such compositions which are easy to use on any type of domestic animal, irrespective of its size and the nature of its coat.
Yet another object of the invention is to provide such compositions which are effective and do not need to be sprinkled over the animal""s entire body.
Yet another object of the invention is to provide such compositions which, when applied locally, will subsequently diffuse over the animal""s entire body and then dry, while at the same time avoiding any phenomenon of crystallization as far as possible.
Yet another object of the invention is to provide such compositions which, after drying, do not affect the appearance of the coat and in particular do not leave crystals and do not make the coat sticky.
These objects are achieved by the invention, the subject of which is antiparasitic compositions which are useful in particular in the treatment and protection of domestic animals which are infested with parasites or are likely to be infested with them, these compositions comprising, in the form of a ready-to-use solution:
a) an insecticidal active substance of formula (I), 
xe2x80x83in which:
R1 is a halogen atom, CN or methyl;
R2 is S(O)nR3 or 4,5-dicyanoimidazol-2-yl or haloalkyl;
R3 is alkyl or haloalkyl, for example lower haloalkyl;
R4 represents a hydrogen or halogen atom; or a radical NR5R6, S(O)mR7, C(O)R7 or C(O)OR7, alkyl, haloalkyl or OR8 or a radical xe2x80x94Nxe2x95x90C (R9) (R10);
R5 and R6 independently represents a hydrogen atom or an alkyl, haloakyl, C(O)alkyl, S(O)rCF3, acyl or alkoxycabonyl radical; or R5 and R6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hereto atoms such as oxygen or sulphur;
R7 represents an alkyl or haloalkyl radical;
R8 represents an alkyl or haloalkyl radical or a hydrogen atom;
R9 represents an alkyl radical or a hydrogen atom;
R10 represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, xe2x80x94O-alkyl, xe2x80x94S-alkyl, cyano or alkyl;
Y represents a halogen atom or a haloalkyl or haloalkoxy radical, for example a lower haloalkoxy radical, or an SF5 radical, with the possibility that:
Y is CN or NO2 in positions 2 and 6 (with reference to the carbon of the phenyl ring which is attached to the pyrazole ring and designated 1);
the carbon in position 2 of the phenyl ring is replaced by a trivalent nitrogen atom;
Y is S(O)qCF3 in position 4 on the phenyl ring, but preferably haloalkyl, haloalkoxy or SF5;
m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2;
p is an integer equal to 1, 2, 3, 4 or 5, preferably equal to 1, 2 or 3, in particular 3;
with the proviso that when R1 is methyl, then either R3 is haloalkyl, R4 is NH2, p is 2, Y in position 6 is Cl, Y in position 4 is CF3 and the carbon in position 2 of the phenyl is replaced by N; or R2 is 4,5-dicyanoimidazol-2-yl, R4 is Cl, p is 3, Y in position 6 is Cl, Y in position 4 is CF3 and the carbon in position 2 of the phenyl is replaced by xe2x95x90Cxe2x80x94Cl,
it being possible for this compound of formula (I) advantageously to be present in the formulation in a proportion of from 1 to 20%, preferably from 5 to 15% (percentages expressed as weight per unit volume=W/V),
b) a crystallization inhibitor which is present, in particular, in a proportion of from 1 to 20% (W/V), preferably from 5 to 15%, this inhibitor satisfying the test according to which: 0.3 ml of a solution A comprising 10% (W/V) of the compound of formula (I) in the solvent defined in c) below, and 10% of this inhibitor, are placed on a glass slide at 20xc2x0 C. for 24 hours, after which few or no crystals, in particularly fewer than 10 crystals, preferably 0 crystals, are seen with the naked eye on the glass slide,
c) an organic solvent having a dielectric constant of between 10 and 35, preferably of between 20 and 30, the content of this solvent c) in the overall composition preferably representing the complement to 100% of the composition,
d) an organic co-solvent having a boiling point below 100xc2x0 C., preferably below 80xc2x0 C., and having a dielectric constant of between 10 and 40, preferably of between 20 and 30; this co-solvent may advantageously be present in the composition in a d) /c) weight/weight (W/W) ratio of between 1/15 and 1/2. The solvent is volatile so as to act in particular as a drying promoter, and is miscible with water and/or with the solvent c).
Preferably, the insecticidal active substance corresponds to formula (II), 
in which:
R1 is a halogen atom, CN or methyl;
R2 is S(O),R3 or 4,5-dicyanoimidazol-2-yl or haloalkyl;
R3 is alkyl or haloalkyl;
R4 represents a hydrogen or halogen atom; or a radical NR5R6, S(O)mR7, C(O)R7 or C(O)OR7, alkyl, haloalkyl or OR8 or a radical xe2x80x94Nxe2x95x90C(R9) (R10);
R5 and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C(O)alkyl, S(O)rCF3 or alkoxy carbonyl radical; or R5 and R6 may together form a divalent alkylene radical which may be interrupted by one or two divalent hetero atoms such as oxygen or sulphur;
R7 represents an alkyl or haloalkyl radical;
R8 represents an alkyl or haloalkyl radical or a hydrogen atom;
R9 represents an alkyl radical or a hydrogen atom;
R10 represents a phenyl or heteroaryl group optionally substituted with one or more halogen atoms or groups such as OH, xe2x80x94O-alkyl, xe2x80x94S-alkyl, cyano or alkyl;
R11 and R12 represent, independently of each other, a hydrogen or halogen atom and possibly CN or NO2, but with H or halogen being preferred;
R13 represents a halogen atom or a haloalkyl, haloalkoxy, S(O)qCF3 or SF5 group;
m, n, q and r represent, independently of each other, an integer equal to 0, 1 or 2;
X represents a trivalent nitrogen atom or a radical Cxe2x80x94R12, the other three valencies of the carbon atom forming part of the aromatic ring;
with the proviso that when R1 is methyl, then either R3 is haloalkyl, R4 is NH2, R11 is Cl, R13 is CF3 and X is N; or R2 is 4,5-dicyanoimidazol-2-yl, R4 is Cl, R11 is Cl, R13 is CF3 and X is xe2x95x90Cxe2x80x94Cl.
The alkyl radicals in the definition of the compounds of formulae (I) and (II) generally comprise from 1 to 6 carbon atoms. The ring formed by the divalent alkylene radical representing R5 and R6, along with the nitrogen atom to which Rs and R6 are attached, is generally a 5-, 6- or 7-membered ring.
As a further preference, R1 is CN, R3 is haloalkyl, R4 is NH2, R11 and R12 are, independently of each other, a halogen atom, and R13 is a haloalkyl. Preferably also, X is Cxe2x80x94R12.
A compound (A) of formula (I) which is most particularly preferred in the invention is 1-[2,6-Cl2 4-CF3 phenyl] 3-CN 4-[SO-CF3] 5-NH2 pyrazole, whose common name is fipronil.
The compounds of formula (I) may be prepared according to one or other of the processes described in patent applications WO-A-87/3781, 93/6089 and 94/21606 or European patent application EP-A-295,117, or any other process which falls within the competence of a specialist skilled in the art of chemical synthesis. For the chemical production of the products of the invention, a person skilled in the art is considered as having at his disposal, inter alia, all of the contents of xe2x80x9cChemical Abstractsxe2x80x9d and of the documents which are cited therein.
Although this is not preferred, the composition may optionally comprise water, in particular in a proportion of from 0 to 30% (volume per unit volume V/V), in particular from 0 to 5%.
The composition may also comprise an antioxidant intended to inhibit aerial oxidation, this agent being present in particular in a proportion of from 0.005 to 1% (W/V), preferably from 0.01 to 0.05%.
The compositions according to the invention intended for pets, in particular cats and dogs, are generally applied by deposition on the skin (xe2x80x9cspot onxe2x80x9d or xe2x80x9cpour onxe2x80x9d application); this is generally a localized application to a region with a surface area of less than 10 cm2, especially between 5 and 10 cm2, in particular at two points and preferably localized between the animal""s shoulders. After deposition, the composition diffuses, in particular over the animal""s entire body, and then dries, without crystallizing or changing the appearance (in particular absence of any whitish deposit or of any dusty appearance) or the feel of the coat.
The compositions according to the invention are particularly advantageous on the grounds of their efficacy, their speed of action and the pleasant appearance of the animal""s hair after application and drying.
As organic solvent c) which can be used in the invention, mention may be made in particular of: acetone, acetonitrile, benzyl alcohol, butyl diglycol, dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether, ethanol, isopropanol, methanol, ethylene glycol monoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, in particular N-methylpyrrolidone, diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalate, or a mixture of at least two of these solvents.
The preferred solvents c) are the glycol ethers, in particular diethylene glycol monoethyl ether and dipropylene glycol monomethyl ether.
As crystallization inhibitor b) which can be used in the invention, mention may be made in particular of:
polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodium carboxymethylcellulose; acrylic derivatives such as methacrylates and the like,
anionic surfactants such as alkaline stearates, in particular sodium, potassium or ammonium stearate; calcium stearate, triethanolamine stearate; sodium abietate; alkyl sulphates, in particular sodium lauryl sulphate and sodium cetyl sulphate; sodium dodecylbenzenesulphonate, sodium dioctylsulphosuccinate; fatty acids, in particular those derived from coconut oil,
cationic surfactants such as water-soluble quaternary ammonium salts of formula N+Rxe2x80x2Rxe2x80x3Rxe2x80x2xe2x80x3Rxe2x80x3xe2x80x3 Yxe2x88x92 in which the radicals R are hydrocarbon radicals, optionally hydroxylated, and Y is an anion of a strong acid such as halide, sulphate and sulphonate anions; cetyltrimethylammonium bromide is among the cationic surfactants which can be used,
amine salts of formula N+Rxe2x80x2Rxe2x80x3Rxe2x80x2xe2x80x3 in which the radicals R are optionally hydroxylated hydrocarbon radicals; octadecylamine hydrochloride is among the cationic surfactants which can be used,
nonionic surfactants such as optionally polyoxyethylenated sorbitan esters, in particular polysorbate 80, polyoxyethylenated alkyl ethers; polyethylene glycol stearate, polyoxyethylenated derivatives of castor oil, polyglycerol esters, polyoxyethylenated fatty alcohols, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide,
amphoteric surfactants such as lauryl-substituted betaine compounds, or preferably a mixture of at least two of these crystallization inhibitors.
In a particularly preferred manner, use will be made of a crystallization inhibitor system, namely the combination of a film-forming agent of polymer type and a surfactant. These agents will be chosen in particular from the compounds mentioned as crystallization inhibitor b).
Among the film-forming agents of polymer type which are particularly advantageous, mention may be made of:
the various grades of polyvinylpyrrolidone,
polyvinyl alcohols, and
copolymers of vinyl acetate and vinylpyrrolidone.
As regards the surfactants, mention will be made most particularly of nonionic surfactants, preferably polyoxyethylenated sorbitan esters and in particular the various grades of polysorbate, for example polysorbate 80.
The film-forming agent and the surfactant may in particular be incorporated in similar or identical amounts within the limit of the total amounts of crystallization inhibitor which are mentioned elsewhere.
The system thus made up achieves, in a noteworthy manner, the aims of absence of crystallization on the hair and of maintenance of the cosmetic appearance of the coat, that is to say without a tendency to stick together or to have a sticky appearance, despite high concentration of active substance.
As co-solvent d), mention may be made in particular of: absolute ethanol, isopropanol (2-propanol), methanol.
As antioxidant, standard agents are used in particular, such as: butylated hydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodium metabisulphite, propyl gallate, sodium thiosulphate, a mixture of not more than two of these antioxidants.
The compositions according to the invention are usually prepared by simply mixing the constituents as defined above; advantageously, to begin with, the active substance is mixed into the main solvent, and the other ingredients or adjuvants are subsequently added.
The subject of the present invention is also a method for the treatment and/or protection (preventive care) of animals against parasites, according to which an effective volume of a composition according to the invention is applied to a limited area of the animal, as is described above. The application is advantageously made at two points and/or on the animal""s back between the shoulders.
The aim of the method may be non-therapeutic, when it concerns cleaning the animal""s hair and skin by eliminating the parasites present as well as their residues and excreta. The animal thus has a coat which is pleasant to look at and to feel. This also makes it possible to prevent the establishment of fleas in the house.
The aim may also be therapeutic when it concerns treating a parasitosis which has pathogenic consequences.
The volume applied may be about 0.3 to 1 ml, preferably about 0.5 ml for cats, and about 0.3 to 3 ml for dogs, depending on the weight of the animal.
The volume of composition applied preferably corresponds to a dose of compound of formula (I) of between 0.3 and 60 mg, in particular of between 5 and 15 mg, per kg.